This invention relates to certain substituted guanidinyl heterocycle compounds. The compounds have been found to be alpha-2 adrenoceptor agonists and are useful for treatment of disorders modulated by alpha-2 adrenoceptors.
Therapeutic indications of alpha-2 adrenoceptor agonists have been discussed in the literature: Ruffolo, R. R., A. J. Nichols, J. M. Stadel, and J. P. Hieble, xe2x80x9cPharmacologic and Therapeutic Applications of Alpha-2 Adrenoceptor Subtypesxe2x80x9d, Annual Review of Pharmacology and Toxicology, Vol. 32 (1993) pp. 243-279.
Information regarding alpha adrenergic receptors, agonists and antagonists, in general, and regarding compounds related in structure to those of this invention are disclosed in the following references: Timmermans, P. B. M. W. M., A. T. Chiu and M. J. M. C. Thoolen, xe2x80x9c12.1 xcex1-Adrenergic Receptorsxe2x80x9d, Comprehensive Medicinal Chemistry, Vol. 3, Membranes and Receptors, P. G. Sammes and J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M. and P. A. van Zwieten,xe2x80x9cxcex1-Adrenoceptor Agonists and Antagonistsxe2x80x9d, Drugs of the Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F. H. L. Awouters and C. J. E. Niemegeers, xe2x80x9cFurther Validation of in vivo and in vitro Pharmacological Procedures for Assessing the xcex11 and xcex12-Selectivity of Test Compounds: (2) xcex1-Adrenoceptor Agonistsxe2x80x9d, European Journal of Pharmacology, Vol.129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink and P. A. van Zwieten, xe2x80x9cQuantitative Relationships between xcex1-Adrenergic Activity and Binding Affinity of xcex1-Adrenoceptor Agonists and Antagonistsxe2x80x9d, Journal of Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans and P. A. van Zwieten, xe2x80x9cSelectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Ratxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith and M. R. Stillings, xe2x80x9cEffect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard xcex1-Adrenoreceptor Agentsxe2x80x9d, European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings and I. F. Tulloch, xe2x80x9cHeteroaromatic Analogues of the xcex12-Adrenoreceptor Partial Agonist Clonidinexe2x80x9d, Journal of Medicinal Chemistry, Vol. 32 (1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton and N. T. Thompson, xe2x80x9cEffects of xcex12-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Plateletsxe2x80x9d, British Journal of Pharmacology, Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319 issued to Danielewicz, Snarey and Thomas on Jun. 17, 1975; and U.S. Pat. No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, many compounds related in structure to those of this invention do not provide the activity and specificity desirable when treating disorders modulated by alpha-2 adrenoceptors.
For example, many compounds found to be effective nasal decongestants are frequently found to have undesirable side effects, such as causing hypertension and insomnia at systemically effective doses. There is a need for new drugs which provide relief from nasal congestion without causing these undesirable side effects.
It is an object of the invention to provide compounds and compositions useful in treating disorders modulated by alpha-2 adrenoceptors.
It is an object of this invention to provide novel compounds having substantial activity in preventing or treating nasal congestion, otitis media, and sinusitis, without undesired side effects.
It is also an object of this invention to provide novel compounds for treating cough, chronic obstructive pulmonary disease (COPD) and/or asthma.
It is also an object of this invention to provide novel compounds for treating diseases and disorders associated with sympathetic nervous system activity, including benign prostatic hypertrophy, cardiovascular disorders comprising myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and hypertension.
It is also an object of this invention to provide novel compounds for treating ocular disorders, such as ocular hypertension, glaucoma, hyperemia, conjunctivitis and uveitis.
It is also an object of this invention to provide novel compounds for treating gastrointestinal disorders, such as diarrhea, irritable bowel syndrome, hyperchlorhydria (hyperacidity) and peptic ulcer (ulcer).
It is also an object of this invention to provide novel compounds for treating migraine.
It is also an object of this invention to provide novel compounds for treating pain, substance abuse and/or withdrawal.
It is a still further object of this invention to provide such compounds which have good activity from peroral, parenteral, intranasal and/or topical dosing.
This invention relates to compounds having the following structure: 
a) R1 is hydrogen; or alkyl or nil; where R1 is nil, bond (a) is a double bond;
b) D is CR2 and R2 is selected from hydrogen; unsubstituted C1-C3 alkanyl; amino, hydroxy, mercapto; C1-C3 alkylthio or alkoxy; C1-C3 alkylamino or C1-C3 dialkylamino and halo; or when B is CR3; D may be N;
c) B is NR9, CR3=CR8, CR3=N, CR3, S, O, SO or SO2; wherein Rg is selected from hydrogen; unsubstituted C1-C3 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; and wherein R3 and R8 are each independently selected from hydrogen; unsubstituted C1-C3 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C1-C3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C1-C3 alkylamino or C1-C3 dialkylamino and halo;
d R4, R5 and R6 are each independently selected from hydrogen; unsubstituted C1-C3 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C1-C3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C1-C3 alkylamino or C1-C3 dialkylamino; halo; and NHxe2x80x94C(=NR10)NHR11 (guanidinyl); wherein R10 and R11 are independently selected from hydrogen; methyl; and ethyl; and wherein one and only one of R4, R5 and R6 is guanidinyl;
e) R7 is selected from hydrogen; unsubstituted C1-C3 alkanyl, alkenyl or alkynyl; cycloalkanyl, cycloalkenyl; unsubstituted C1-C3 alkylthio or alkoxy; hydroxy; thio; nitro; cyano; amino; C1-C3 alkylamino or C1-C3 dialkylamino and halo;
and enantiomers, optical isomers, stereoisomers, diastereomers, tautomers, addition salts, biohydrolyzable amides and esters, and pharmaceutical compositions containing such novel compounds, and the use of such compounds for preventing or treating disorders modulated by alpha-2 adrenoceptors.
As used herein, xe2x80x9calkanylxe2x80x9d means a saturated hydrocarbon substituent, straight or branched chain, unsubstituted or substituted.
As used herein, xe2x80x9calkenylxe2x80x9d means a hydrocarbon substituent with one double bond, straight or branched chain, unsubstituted or substituted.
As used herein, xe2x80x9calkylthioxe2x80x9d means a substituent having the structure Qxe2x80x94Sxe2x80x94, where Q is alkanyl or alkenyl.
As used herein, xe2x80x9calkoxyxe2x80x9d means a substituent having the structure Qxe2x80x94Oxe2x80x94, where Q is alkanyl or alkenyl.
As used herein, xe2x80x9calkylaminoxe2x80x9d means a substituent having the structure Qxe2x80x94NHxe2x80x94, where Q is alkanyl or alkenyl.
As used herein, xe2x80x9cdialkylaminoxe2x80x9d means a substituent having the structure Q1xe2x80x94N(Q2)xe2x80x94, where each Q is independently alkanyl or alkenyl.
xe2x80x9cGuanidinylxe2x80x9d is defined as a radical of structure; 
For purposes of exemplifying this radical, wherever it appears in a chart, it is shown as xe2x80x9cGNDNLxe2x80x9d for brevity.
xe2x80x9cHaloxe2x80x9d, xe2x80x9chalogenxe2x80x9d, or xe2x80x9chalidexe2x80x9d is a chloro, bromo, fluoro or iodo.
A xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987, incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates, and the like. Clearly contemplated in such salts are addition salts that may provide an optical center, where once there was none. For example, a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts.
The compounds of the invention are sufficiently basic to form acid-addition salts. The compounds are useful both in the free base form and the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts are in some cases a more convenient form for use. In practice, the use of the salt form inherently amounts to the use of the base form of the active. Acids used to prepare acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts. These salts have anions that are relatively innocuous to the animal organism, such as a mammal, in medicinal doses of the salts so that the beneficial property inherent in the free base are not vitiated by any side effects ascribable to the acid""s anions.
Examples of appropriate acid-addition salts include, but at not limited to hydrochloride, hydrobromide, hydroiodiode, sulfate, hydrogensulfate, acetate, trifluoroacetate, nitrate, maleate, citrate, fumarate, formate, stearate, succinate, mallate, malonate, adipate, glutarate, lactate, propionate, butyrate, tartrate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate, cyclohexanesulfamate, and the like. However, other appropriate medicinally acceptable salts within the scope of the invention are those derived from other mineral acids and organic acids. The acid-addition salts of the basic compounds are prepared by several methods. For example the free base can be dissolved in an aqueous alcohol solution containing the appropriate acid and the salt is isolated by evaporation of the solution. Alternatively, they may be prepared by reacting the free base with an acid in an organic solvent so that the salt separates directly. Where separation of the salt is difficult, it can be precipitated with a second organic solvent, or can be obtained by concentration of the solution.
Although medicinally acceptable salts of the basic compounds are preferred, all acid-addition salts are within the scope of the present invention. All acid-addition salts are useful as sources of the free base form, even if the particular salt per se is desired only as an intermediate product. For example, when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a medicinally acceptable salt by ion exchange procedures, these salts are clearly contemplated to be a part of this invention.
xe2x80x9cBiohydrolyzable amidexe2x80x9d refers to an amide of the compound of the invention that is readily converted in vivo by a mammal subject to yield an active compound of the invention.
A xe2x80x9cbiohydrolyzable esterxe2x80x9d refers to an ester of the compound of the invention that is readily converted by a mammal subject to yield an active compound of the invention.
xe2x80x9cOptical isomerxe2x80x9d, xe2x80x9cstereoisomerxe2x80x9d, xe2x80x9cenantiomer,xe2x80x9d xe2x80x9cdiastereomer,xe2x80x9d as referred to herein have the standard art recognized meanings (Cf., Hawleys Condensed Chemical Dictionary, 11th Ed.). Of course, an addition salt may provide an optical center, where once there was none. For example, a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts. It will be apparent to the skilled artisan that disclosure of the racemic mixture alone discloses any enantiomers therein. Thus by one disclosure, more than one compound is taught.
As used herein xe2x80x9canimalxe2x80x9d includes xe2x80x9cmammalsxe2x80x9d which includes xe2x80x9chumansxe2x80x9d.
The skilled artisan will appreciate that tautomeric forms will exist in certain compounds of the invention. For example, when R2 is hydroxy and bond (a) is a double bond, it is understood to include the keto form of that molecule, where R2 is oxo, and bond (a) is a single bond, though not specifically described. Thus, in this description the disclosure of one tautomeric form discloses each and all of the tautomers. Similarly, when tautomer A of the molecule is shown, it is understood to include tautomers B and C of that molecule although not specifically depicted. 
The illustration of specific protected forms and other derivatives of the Formula (I) compounds is not intended to be limiting. The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.
As defined above and as used herein, substituent groups may themselves be substituted. Such substitution may be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated by reference herein. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro, amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy, alkoxyacetyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof.
For the purposes of nomenclature, as shown in the following example, the location of the guanidinyl radical is: 
It is recognized that where B is CR3=CR8 and the like, this numbering is not in strict compliance with IUPAC nomenclature. It is used for illustration of synthetic methods only; examples of compounds have names which more closely resemble IUPAC nomenclature.
This invention includes compounds having the following structure: 
as described in the Summary of the Invention.
In the above structure, when the guanidinyl is at the 6-position, preferably R7 is selected from hydrogen; unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano; and halo. R4 is preferably hydrogen, cyano, halo or methyl. R7 is also preferably alkanyl, more preferably methyl or ethyl, most preferably methyl. R7 which is alkylthio or alkoxy is preferably saturated, also preferably C1 or C2, most preferably methylthio or methoxy. R7 which is halo is preferably chloro or bromo.
In the above structure, when the guanidinyl is at the 5-position, preferably R4 is selected from hydrogen; unsubstituted alkanyl or alkenyl having 1 to about 3 carbon atoms; unsubstituted alkylthio or alkoxy having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano; and halo. R7 is preferably alkanyl or halo. R4 and R7 are most preferably methyl.
In the above structure, when the guanidinyl is at the 4-position, preferably R7 is selected from hydrogen; unsubstituted alkanyl or alkenyl having from 1 to about 3 carbon atoms; hydroxy; thiol; cyano; and halo. R7 which is alkanyl, is preferably methyl or ethyl, more preferably methyl. R7 which is halo is preferably chloro or bromo. R6 is preferably hydrogen; alkanyl; cyano; and halo. R6 which is alkanyl is preferably methyl or ethyl, most preferably methyl. R5 is preferably hydrogen; alkanyl; and halo. R5 which is alkanyl is preferably methyl or ethyl, most preferably methyl.
Preferred compounds of this invention have the following structure: 
where R1 is nil, (a) is a double bond and D, B, R4, R5, R7 and R10 are as indicated in the following table:
The compounds of this invention are synthesized using the following procedures. For purposes of this description, 6-guanidinyl compounds are shown, but the skilled artisan will appreciate that the 4- and 5-guanidinyl compounds are prepared similarly. The R1-R7 radicals are omitted for clarity, unless they are prepared in that specific scheme. The skilled artisan will appreciate that the radicals omitted are added using techniques known in the art. The skilled artisan will also appreciate that the methods described may be used with blocking groups and the like, as appropriate.
Guanidinyl groups are conveniently prepared from nitro and amino compounds via the following example synthetic sequences: 
Preferably these compounds are made from nitro or amino compounds. (Nitro and amino compounds are made by known processes.) The compounds may be manipulated to result in the suitably substituted aminoheterocycle. This aminoheterocycle is then subjected to known methods to produce the guanidinyl derivative. For example, the amino compound may be reacted with cyanamide (H2NCN) in acid to provide the guanidinyl compound. Alternatively, the amino compound may be reacted with a guanidine precursor, such as an alkyl pseudothiourea or protected alkyl pseudothiourea in the presence of a mercuric salt or the like.
The above starting nitro and amino compounds are obtained via one or more synthetic steps comprising alkylations, halogenations (usually brominations), and halogen displacement reactions. These reaction types are summarized below;



Preferably, chlorination is accomplished using Cl2, and iodination, by ICl using the same reactions.

It will be apparent to the skilled artisan that the reactions illustrated above are known reactions. Furthermore, it is within the purview of the skilled artisan to vary these reactions to prepare compounds within the scope of the claims.
In the above schemes, where an R is alkoxy or alkylthio, the corresponding hydroxy or thiol compounds are derived from the final compounds by using a standard dealkylating procedure (Bhatt, et al., xe2x80x9cCleavage of Ethersxe2x80x9d, Synthesis, 1983, pp. 249-281).
The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available as a starting material.
It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterifications and saponifications and the like. These manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (2 vol.) and Trost and Fleming Comprehensive Organic Synthesis (6 vol.). The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations are found, for example, in T. Greene, Protecting Groups in Organic Synthesis.